A genomically-tailored multi-agent precision medicine clinical trial for adults with recurrent glioblastoma.

Abstract

Existing salvage therapies for recurrent glioblastoma (rGBM) have limited efficacy, with median survival of approximately 9 months. Given the complex molecular heterogeneity of GBM, single-target approaches have consistently failed as a treatment strategy. We conducted a phase 1 clinical trial to assess the feasibility, safety, and efficacy of a genomically-tailored multi-agent regimen in 30 adults with surgically-treated rGBM. Adults with IDH-wildtype glioblastoma (n=29) or grade 4 IDH-mutant astrocytoma (n=1) were consented and underwent clinically-indicated surgery for recurrent disease. Comprehensive genomic profiling was performed on the recurrent tumors, and results for each patient were discussed at an individualized molecular tumor board to determine a personalized treatment regimen combining up to 4 FDA-approved drugs, including one cytotoxic agent as backbone. A total of 12 drugs were used in 18 combinations - the most common regimen was lomustine, afatinib, and abemaciclib (n=8). The most common toxicities included cytopenias, rash, and gastrointestinal symptoms, requiring frequent dose reductions. Measured from surgery at trial enrollment, progression-free survival at 6 months (PFS-6) was 40%, overall survival at 9 months (OS-9) was 73%, and median OS was 12.7 months. After trial therapy, genomic profiling performed on subsequent recurrent tumor specimens identified genetic evolution corresponding to putative treatment resistance mechanisms. Implementation of individualized treatment regimens in a timely fashion was feasible for patients with surgically resectable rGBM. Overall efficacy was not significantly improved compared to a contemporary patient cohort treated without experimental regimens, with full dosing of most combination therapies limited by toxicities.